1 . Field of the Invention
The invention relates to a method of producing (S)-cyanohydrins with the general formula I ##STR3## in which the groups R and R' signify, independently of one another: Hydrogen;
A substituted or unsubstituted, linear or branched, saturated alkyl group with 1 to 18 C atoms which can comprise one or several amine, imine, hydroxy, C.sub.1 -C.sub.8 -alkoxy, halogen, carboxyl, C.sub.3 -C.sub.20 -cycloalkyl groups and/or one optionally N,O,S-heteroatom-substituted aromatic ring with up to 22 C atoms as substituent, which cyclic substituents can be substituted themselves singly or multiply with halogen, hydroxy and/or linear or branched C.sub.1 -C.sub.8 -alkyl or C.sub.2 -C.sub.8 -alkenyl or C.sub.2 -C.sub.8 -alkinyl; PA1 A substituted or unsubstituted, linear or branched, singly or multiply unsaturated alkenyl- or alkinyl group with 2 to 18 C atoms which can comprise one or several amine, imine, hydroxy, C.sub.1 -C.sub.8 -alkoxy, halogen, carboxyl, C.sub.3 -C.sub.20 -cycloalkyl groups and/or one optionally N,O,S-heteroatom-substituted aromatic ring with up to 22 C atoms as substituents, which cyclic substituents can be substituted themselves singly or multiply with halogen, hydroxy and/or linear or branched C.sub.1 -C.sub.8 -alkyl or C.sub.2 -C.sub.8 -alkenyl or C.sub.2 -C.sub.8 -alkinyl; PA1 A substituted or unsubstituted aromatic or heteroaromatic group with 5 to 22 ring atoms in which up to 4 of the ring carbon atoms can be replaced by N, O and/or S and the group can comprise one or several amine, imine, hydroxy, C.sub.1 -C.sub.8 -alkoxy, aryloxy, halogen, carboxy and/or linear or branched, saturated or singly or multiply unsaturated alkyl groups with one to 22 C atoms as substituent and at least two of the substituents on the ring can be joined to a cycle, PA1 provided that R and R' do not signify hydrogen at the same time, by enzyme-catalyzed conversion of carbonyl compounds of general formula II ##STR4## in which R and R' have the meaning indicated for formula I, with hydrogen cyanide or a substance supplying hydrogen cyanide or CN.sup.- for the reaction in the presence of an amount of an immobilized (S)-oxynitrilase which catalyses the reaction.
2. Background Information
Starting from chiral cyanohydrins, a plurality of important substance classes of optically active compounds such as e.g. .alpha.-amino alcohols, .alpha.-hydroxyaldehydes and .alpha.-hydroxycarboxylic acids are readily accessible. Methods for producing optically active (S)-cyanohydrins are described in the literature.
The enantioselective addition of trimethylsilyl cyanide in the presence of chiral catalysts plays a significant part in the chemical methods for the synthesis of optically active cyanohydrines.
According to H. Minamikawa, S. Hayakawa, T. Yamada, N. Iwasawa, K. Narasake, Bull. Chem. Soc. Jpn. 61 (1988), 4379 and K. Narasaka, T. Yamada, H. Minamikawa, Chem. Lett. 1987, 2073 the (R)-cyanohydrins are produced starting from a few aliphatic and aromatic aldehydes in good chemical and optical yields (61-93% ee). The authors indicate that the (S)-cyanohydrins are formed when using the corresponding other enantiomer of the catalyst.
According to M. Hayashi, T. Matsuda, N. Oguni, J. Chem. Soc. Chem. Commun. 1990, 1364 titanium tetraisopropanolate with L(+)-diisopropyltartrate or with chiral Schiff bases was used as a further chiral catalyst (M. Hayashi, Y. Miyamoto, T. Inoue, N. Oguni, J. Org. Chem. 58 (1993), 1515). Depending on the catalyst used, both aromatic as well as aliphatic (S)- and (R)-cyanohydrins were produced usually in unsatisfactory enantiomeric excesses of 22-96% ee.
According to E. J. Corey, Z. Wang, Tetrahedron Lett. 34 (1993), 4001, it was possible to obtain a few aliphatic (S)-cyanohydrins by cyanosilylizing in very good chemical and optical yields (ee values up to 95% for heptanal) with a bisoxazoline magnesium complex as chiral catalyst.
Good enantiomeric excesses can also be obtained in the diastereoselective cyanosilylizing of aldehydes acetalized with 2(R),4(R)-pentanediol. According to J. D. Elliot, V. Choi, W. P. Johnson, J. Org. Chem. 48 (1983), 2294 an ee value of 93% at a 97% yield was achieved thereby for (R)-mandelonitrile. If the corresponding 2(S),4(S)-pentanediol is used (S)-cyanohydrin is produced in the same manner.
Even optically active, protected a-amino aldehydes (M. T. Reetz, M. W. Drewes, K. Harms, W. Reif, Tetrahedron Lett. 29 (1988), 3295; J. Herranz, J. Castro-Pichel, T. Gracia-Lopez, Synthesis 1989, 703) and .alpha.-hydroxy aldehydes (M. T. Reetz, K. Kesseler, A. Jung, Angew. Chem. 97 (1985), 989) can be converted under Lewis acid-catalysis with trimethylsilyl cyanide or tributyl tin cyanide under moderate to good diastereoselectivity into the corresponding .beta.-amino-.alpha.-hydroxy- and .alpha.,.beta.-dihydroxynitriles.
A further possibility for synthesizing (S)-cyanohydrins starting from (R)-cyanohydrins is known from F. Effenberger, U. Stelzer, Angew. Chem. 103 (1991), 866 and F. Effenberger, U. Stelzer, Chem. Ber. 126 (1993), 779.
The (R)-cyanohydrins are sulfonylized thereby and then reacted with potassium acetate under S.sub.N 2 conditions. The acetyl group is removed in the aqueous sour leaven!. In the case of aliphatic cyanohydrins all stages take place totally free of racemization; racemization occurs in part at times! in the case of aromatic cyanohydrins. This method can be used especially for those compounds which were not directly accessible since that time on account of the limited substrate spectrum of the (S)-oxynitrilases.
The Mitsunobu reaction also takes place under the inversion of (R)-cyanohydrins (E. Warmerdam, J. Brussee, C. G. Kruse, A. van der Gen, Tetrahedron 49 (1993), 1063).
However, when viewed on the whole it is desirable in every instance to replace the chemical methods by enzyme-catalyzed methods. (R)-cyanohydrins with very differing structure are accessible in very good optical yields via the addition of hydrogen cyanide to aldehydes catalyzed with hydroxynitrile lyase from bitter almonds (PaHNL) (EC 4.1.2.10) (F. Effenberger, Angew. Chem. 1994, 106, 1690-1619). Since the enzyme is also readily accessible in industrial amounts, this method offers the simplest access to (R)-cyanohydrins.
However, the conditions for the enzyme-catalyzed preparation of (S)-cyanohydrins are considerably different. The use of hydroxynitrile lyase from bicolor sorghum (SbHNL) (EC 4.1.2.11) as catalyst has proven to be the most successful (F. Effenberger, B. Horsch, S. Forster, T. Ziegler, Tetrahedron Lett. 1990, 31, 1249-1252; U. Niedermeyer, M. -R. Kula, Angew. Chem. 1990, 102, 423-425; Angew. Chem. Int. Ed. Engl. 1990, 29, 386-387; M. -R. Kula, U. Niedermeyer, I. M. Stuertz, EP-B 350,908, 1990; DE-B 38 23 866 (Chem. Abstr. 1990, 113, 57462h)), an enzyme which in the meantime can also be obtained from millet seedlings in amounts sufficient for synthetic applications. In addition to the rather difficult accessibility, the substrate spectrum of SbHNL, which is distinctly limited in comparison to PaHNL and accepts only aromatic and heteroaromatic aldehydes as substrates, is a serious disadvantage for the use of this enzyme.